cystatines

Cystatins are a superfamily of cysteine protease inhibitors that regulate proteolysis in virtually all organisms. They inhibit a broad range of cysteine proteases, including cathepsins B, L, and S, and papain-like enzymes, helping control processes such as protein turnover, antigen presentation, inflammation, and extracellular matrix remodeling. Cystatins are present in intracellular and extracellular compartments and are found in many body fluids, secretions, and tissues.

Three main subfamilies are recognized: type 1 stefins (A and B) are small intracellular proteins lacking signal peptides and disulfide bonds; type 2 cystatins are secreted glycoproteins found in saliva, blood, and cerebrospinal fluid; type 3 cystatins, also known as kininogens, are high-molecular-weight, multi-domain proteins circulating in blood that function as cysteine protease inhibitors and interact with the kallikrein-kinin system.

Key members include cystatin C (CST3), a widely used serum biomarker of kidney function, and cystatin B (stefin B), mutations of which cause progressive myoclonus epilepsy (Unverricht-Lundborg disease). Cystatin C is valued in clinical practice for its relative independence from muscle mass compared with creatinine.

Inhibition occurs via non-covalent binding to target proteases, using a reactive center region and N-terminal segment to block the active site, forming a stable complex and preventing substrate cleavage. Cystatins are studied as disease biomarkers and potential therapeutic regulators of proteolysis in cancer, neurodegeneration, and inflammatory diseases; their levels and activity reflect tissue homeostasis and inflammatory status.